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Expression and Prognostic Significance of IAP-Family Genes in Human Cancers and Myeloid Leukemias¹

The Burnham Institute, La Jolla, California 92037 [I. T., S. K., K. W., S. K., J. C. R.]; University of Texas, M. D. Anderson Cancer Center, Houston, Texas 77030 [S. M. K., H. S., Y. H. Q., M. A.]; and National Cancer Institute, Developmental Therapeutics Program, Frederick Cancer Research and Development Center, Frederick, Maryland [D. A. S., G. T., A. M.]

Expression of several inhibitor of apoptosis proteins (IAPs) was investigated in the National Cancer Institute panel of 60 human tumor cell lines, and the expression and prognostic significance of one of these, XIAP, was evaluated in 78 previously untreated patients with acute myelogenous leukemia (AML). XIAP and cIAP1 were expressed in most cancer lines analyzed, with substantial variability in their relative levels. In contrast, NAIP mRNA was not detectable, and cIAP2 was found at the mRNA and protein levels in only 34 (56%) and 5 (8%) of the 60 tumor cell lines analyzed, respectively. Interestingly, XIAP, cIAP1, and cIAP2 mRNA levels did not correlate with protein levels in the tumor lines, indicating posttranscriptional regulation of expression. High levels of XIAP protein in tumor cell lines were unexpectedly correlated with sensitivity to some anticancer drugs, particularly cytarabine and other nucleosides, whereas higher levels of cIAP1 protein levels were associated with resistance to several anticancer drugs. The relevance of XIAP to in vivo responses to cytarabine was explored in AML, making correlations with patient outcome (n = 78). Patients with lower levels of XIAP protein had significantly longer survival (median, 133 versus 52.5 weeks; P = 0.05) and a tendency toward longer remission duration (median, 87 versus 52.5 weeks; P = 0.13) than those with higher levels of XIAP. Altogether, these findings show that IAPs are widely but differentially expressed in human cancers and leukemias and suggest that higher XIAP protein levels may have adverse prognostic significance for patients with AML.

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				I. Imoto, Z.-Q. Yang, A. Pimkhaokham, H. Tsuda, Y. Shimada, M. Imamura, M. Ohki, and J. Inazawa Identification of cIAP1 As a Candidate Target Gene within an Amplicon at 11q22 in Esophageal Squamous Cell Carcinomas Cancer Res., September 1, 2001; 61(18): 6629 - 6634. [Abstract] [Full Text] [PDF]

				C. G. Ferreira, P. van der Valk, S. W. Span, I. Ludwig, E. F. Smit, F. A. E. Kruyt, H. M. Pinedo, H. van Tinteren, and G. Giaccone Expression of X-linked Inhibitor of Apoptosis as a Novel Prognostic Marker in Radically Resected Non-Small Cell Lung Cancer Patients Clin. Cancer Res., August 1, 2001; 7(8): 2468 - 2474. [Abstract] [Full Text] [PDF]

				M. MANDERSCHEID, U. K. MEßMER, R. FRANZEN, and J. PFEILSCHIFTER Regulation of Inhibitor of Apoptosis Expression by Nitric Oxide and Cytokines: Relation to Apoptosis Induction in Rat Mesangial Cells and RAW 264.7 Macrophages J. Am. Soc. Nephrol., June 1, 2001; 12(6): 1151 - 1163. [Abstract] [Full Text]

				B. Z. Carter, M. Milella, D. C. Altieri, and M. Andreeff Cytokine-regulated expression of survivin in myeloid leukemia Blood, May 1, 2001; 97(9): 2784 - 2790. [Abstract] [Full Text] [PDF]

				J. C. Reed Mechanisms of Apoptosis Am. J. Pathol., November 1, 2000; 157(5): 1415 - 1430. [Abstract] [Full Text] [PDF]

				J. T. Isaacs Apoptosis: Translating Theory to Therapy for Prostate Cancer J Natl Cancer Inst, September 6, 2000; 92(17): 1367 - 1369. [Full Text] [PDF]

				G. M. Kasof and B. C. Gomes Livin, a Novel Inhibitor of Apoptosis Protein Family Member J. Biol. Chem., January 26, 2001; 276(5): 3238 - 3246. [Abstract] [Full Text] [PDF]

				G.-Q. Wang, B. R. Gastman, E. Wieckowski, L. A. Goldstein, A. Rabinovitz, X.-M. Yin, and H. Rabinowich Apoptosis-resistant Mitochondria in T Cells Selected for Resistance to Fas Signaling J. Biol. Chem., January 26, 2001; 276(5): 3610 - 3619. [Abstract] [Full Text] [PDF]